The fibrates are a group of drugs which are known as hypolipidaemic agents. They include bezafibrate, ciprofibrate, fenofibrate and gemfibrizol. The fibrates have the beneficial effect of lowering cholesterol levels in the blood and hence reducing the risk of coronary heart disease (CHD). Epidemiological studies have confirmed that elevated cholesterol is one of the most important risk factors of coronary heart disease. It accelerates the development of atherosclerosis and enhances the adverse effects of other risk factors such as smoking, obesity, diabetes and hypertension. Reducing elevated cholesterol levels lowers the incidence of coronary death and non-fatal myocardial infarction. The lipoproteins which carry cholesterol are classified according to their density: very low density lipoproteins (VLDL); low density lipoproteins (LDL); and high density lipoproteins (HDL). About 70% of the plasma total cholesterol is carried in the LDL fraction and the major atherogenic potential appears to be mediated by this fraction. HDL is generally regarded as having a protective effect. Fibrates reduces plasma LDL, VLDL and total triglycerides and raise plasma HDL.
The fibrates are currently only available as solid dosage forms. Thus for example, fenofibrate is commercially available in micronised form, formulated as capsules (LIPANTIL MICRO™) or tablets (SUPRALIP™) which formulations are indicated for the treatment of types IIa, IIb, III, IV and V hyperlipidaemia resistant to diet; the tablets are also indicated for use in dyslipidaemia in diabetes.
Fibrates have extremely low solubility in water. Thus for example fenofibrate has a solubility in water of around 6 μg/ml. This can adversely affect absorption of the drug substance in vivo, leading to poor bioavailability. Consequently higher amounts of the drug substance are required to achieve the desired blood levels. The poor solubility of the fibrates also restricts the options available for formulating the drug substance.
Following oral administration, the absorption of drugs from the intestine is mainly dependent on their solubility in the intestinal fluids and their intestinal permeability. Poorly soluble drugs generally have low dissolution rates and exhibit only a small concentration gradient across the intestinal mucosa, which can result in low and unreliable levels of absorption. Drug substances which have low solubility also suffer from disadvantages in respect of other routes of administration, for example, by injection. Thus, it may only be possible to achieve very dilute solutions which do not provide the required dosage. In such circumstances it may be necessary to administer the drug as a continuous infusion rather than as a bolus injection. In some cases it may not be possible to achieve formulations suitable for parenteral administration at all.
Thus, because of its physicochemical characteristics, mainly its poor water solubility, fenofibrate has a low bioavailability and furthermore, a huge difference between bioavailability in fasted and in fed conditions can be observed. This difference is known as the ‘food effect’. Many different approaches have been tried in order to overcome these problems.
EP A 0330532 describes the co-micronization of fenofibrate with a surfactant, preferably sodium lauryl sulfate, which composition is said to have improved bioavailability. A similar improvement in biavailability was reported in WO 96/21439, which describes formulations of fenofibrate consisting of a semi solid matrix based on “lauroyl macrogolglycerides” (Gelucire 44/14®) However neither of these approaches provides 100% bioavailability and the “food effect” behavior was not solved.
An alternative approach is described in U.S. Pat. No. 6,180,138 in which the fenofibrate is comicronized with an hydrophilic ingredient prior mixing with a surfactant. The product is finally spray dried to provide a powder useful for tablets or capsules formulations.
WO 98/31361 teaches how to obtain a granulate of fenofibrate combined with a hydrophilic polymer and a surfactant. This process requires large amount of diluent and thus is not compatible with high dosages.
Moreover, WO 00/16749 describes the preparation of fenofibrate granules using wet granulation combining water and water miscible solvent.
U.S. Pat. No. 5,880,148 describes compositions which comprise a micronised mixture of fenofibrate with a solid surfactant, preferably sodium lauryl sulphate, and a vitamin E substance selected from tocopherols and their esters with organic acids. The preferred vitamin E substance is said to be dl-alpha-tocopherol acetate.
Self emulsifying drug delivery systems (SEDDS) as described in WO 99/29300 represent another approach to formulating drugs with low bioavailability. Thus, WO 99/29300 describes compositions of fenofibrate in a carrier system comprising a hydrophobic component, eg a glyceride, a hydrophilic component eg a polyethylene glycol and a surfactant. Also described is a self-emulsifying preconcentrate which comprises an oil phase, eg a glyceride, a surfactant phase comprising at least one non-ionic surfactant and a hydrophilic component eg a PEG. The surfactant may be inter alia vitamin E TPGS. In these compositions the fenofibrate is solubilised in the oil phase. However, these systems require high concentrations of surfactant in order to dissolve the active substance in the oil in a sufficent amount and to obtain the self-formation of a fine emulsion or a microemulsion upon dilution in the gastric fluid. Most of the time the payload which can be achieved is limited and not compatible with high doses. Moreover, the addition of ethanol or propylene glycol to this oil-based formulation in order to help drug dissolution and overcome crystallisation problems makes this formulation incompatible with hard shell of soft gel capsule presentations.
WO 01/49262 describes pre-emulsion concentrates of fenofibrate comprising a lipophilic phase preferably containing an oil based on glycerol or propylene glycerol esters; an emulsifying system containing a lipophilic surfactant and a hydrophilic co-surfactant and further comprising vitamin E acetate to stabilize the pre-concentrate. In these compositions, the fenofibrate is solubilised in the oil phase. The formulations may additionally contain vitamin E TPGS as a surfactant. It is reported in WO 01/49262 that the use of vitamin E acetate aids drug dissolution and inhibition of crystallization and thus obviates the use, of ethanol or propylene glycol.
Vitamin E TPGS is known to form liquid crystals at concentrations above 20% and in U.S. Pat. No. 5,891,845 tablets are formulated using this compound in order to utilise the advantages of the high solubilization power of the liquid crystalline phase. These formulations contain at least 50% vitamin E TPGS, eg 80% and above.
More generally oils and vitamins E TPGS have been described several times in patents as bioavailability enhancer (U.S. Pat. No. 6,121,234; U.S. Pat. No. 6,028,054; U.S. Pat. No. 6,096,338) and in public presentations (“Vit E TPGS as an emulsifier and a bioenhancer for drugs and lipophilic compounds” Adams, M W 6th international conference on Pharmaveutical Technology Paris Jun. 2-4, 1992.) According to Eastman brochure (www.Eastman.com/Online_Publications/efc226a/efc22611.htm) using vit E TPGS as a vitamin E supplement provides enhanced bioavailability of vitamin E in animals and humans.
Significant efforts have been directed to producing drug substances in the form of microparticles and nanoparticles. However, preparation of such small particles is not a trivial matter and can give rise to further difficulties both in relation to technical aspects of the process and in obtaining a satisfactory product. Thus for example there can be difficulties, especially on a manufacturing scale in obtaining a consistent and narrow particle size range. Furthermore, it is necessary to obtain stable products, e.g. nanosuspensions, but microparticles and nanoparticles have a tendency to aggregate and flocculate, which has adverse consequences for the stability of the product. A number of different approaches have been investigated for the preparation of microparticles and nanoparticles.
U.S. Pat. No. 5,091,188 describes a method for preparing injectable solutions of water-insoluble drugs, which comprises reducing the crystalline drug substance to dimensions in the range 50 nm to 10 μm, by sonication or other processes inducing high shear, in the presence of a phospholipid or other membrane-forming amphipathic lipid, whereby the drug microcrystals become coated with said lipid.
U.S. Pat. No. 5,145,684 describes particles of crystalline drug substance having a non-cross linked surface modifier adsorbed on the surface and an effective average particle size of less than about 400 nm. These particles are said to be prepared by milling in the presence of grinding media, using for example a ball mill, an attrition mill, a vibratory mill or a media mill.
International Patent Application WO 96/14830 (U.S. Pat. No. 5,858,410) describes a drug carrier which comprises particles of a pure active compound which is insoluble or only sparingly soluble in water, which has an average diameter of 10 nm to 1,000 nm and the proportion of particles larger than 5 μm in the total population is less than 0.1%. Preparation of the particles, with or preferably without surfactant, by means of cavitation (e.g. using a piston-gap homogenizer) or by shearing and impact forces (i.e. the jet stream principle) is also described.
WO 00/30616 describes particle size reduction of fenofibrate using high pressure homogenization down to mean particle size of 0.91 μm. The stabilization of the system is obtained by using phospholipids combined with ionic or non-ionic surfactants. This application also describes how to obtain freeze dried product able to regenerate the nanosuspension upon dilution in the appropriate solvent. WO 00/30615 decribes similar suspension formulations. Particles with a mean diameter around 900 nm are obtained; however only formulations combining at least one phospholipid with another surfactant are stable. Fenofibrate suspensions stabilized using only phospholipids are reported as not stable.
Another approach of fenofibrate fine particle design is described in WO 99/65469 where supercritical fluid technology allows the manufacturing of particles having a mean diameter of 200 nm. Once again, the particle manufacturing requires the use of a mixture of phospholipids and ionic or non ionic surfactants. The limited solubility of fenofibrate in supercritical fluid could be an hurdle for high doses requirements because of the quantities of liquefied gaz which will be necessary to process.
International application WO 00/51572 describes the use of PEG-derivatized lipids as surface stabilizers for nanoparticulate compositions of poorly soluble drugs. The PEG-derivatised lipid may be a PEG-phospholipid, PEG-cholesterol, PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, or a mixture thereof. It is stated that the invention can be practiced with a wide variety of drugs, and various classes of drugs are listed; there is no specific reference to hypolipidaemic agents. However, it appears from the only example using PEG vit E derivative that this compound does not provide the expected result. As stated in the conclusion of this example, “none of the tested surfactants (in vit E PEG) resulted in a stable non agglomerated nanoparticulate composition.”